Inherited genetics of adult diffuse glioma and polygenic risk scores-a review

Abstract

Knowledge about inherited and acquired genetics of adult diffuse glioma has expanded significantly over the past decade. Genomewide association studies (GWAS) stratified by histologic subtype identified six germline variants that were associated specifically with glioblastoma (GBM) and 12 that were associated with lower grade glioma. A GWAS performed using the 2016 WHO criteria, stratifying patients by IDH mutation and 1p/19q codeletion (as well as TERT promoter mutation), discovered that many of the known variants are associated with specific WHO glioma subtypes. In addition, the GWAS stratified by molecular group identified two additional novel regions: variants in D2HGDH that were associated with tumors that had an IDH mutation and a variant near FAM20C that was associated with tumors that had both IDH mutation and 1p/19q codeletion. The results of these germline associations have been used to calculate polygenic risk scores, from which to estimate relative and absolute risk of overall glioma and risk of specific glioma subtypes. We will review the concept of polygenic risk models and their potential clinical utility, as well as discuss the published adult diffuse glioma polygenic risk models. To date, these prior genetic studies have been done on European populations. Using the published glioma polygenic risk model, we show that the genetic associations published to date do not generalize across genetic ancestries, demonstrating that genetic studies need to be done on more diverse populations.

Keywords: genetics; glioma; polygenic; risk; variants.

Figure 1.

Summary of the 27 adult diffuse glioma germline risk variants reported from GWAS studies. Pink, green and black denotes variants associated with risk of IDH-mutant glioma, IDH-wildtype glioma, or all glioma, respectively. The TERT and EGFR variants are denoted by both green and pink. These two variants were historically associated with IDH wildtype tumors; however, there is evidence to suggest that they are also associated with specific IDH-mutated tumors.

Figure 2.

A summary of the glioma polygenic risk model that was developed using 25 risk variants, where β_j denotes the logarithm transformed odds ratio for the j^th risk variant and variant_j denotes the number of risk alleles for the j^th risk variant. A risk score is calculated for all individuals and subsequently individuals are assigned to risk score percentile categories. MS, Multiple Sclerosis.

Figure 3.

Polygenic risk scores for adult IDH-mutant noncodeleted glioma. (a) Risk score distributions from glioma cohorts of European and non-European ancestries. (b) Risk score distributions from nonglioma cohorts of European ancestry, including individuals in TCGA with primary tumor locations that are known to have the potential to metastasize to the brain. (c) Risk score distributions from nonglioma cohorts of non-European ancestry, including individuals in TCGA with primary tumor locations that are known to have the potential to metastasize to the brain. BRCA, Breast invasive carcinoma; CLL, chronic lymphocytic leukemia; COAD, colon adenocarcinoma; KIRC, kidney renal clear cell carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; READ, rectum adenocarcinoma; TCGA, The Cancer Genome Atlas.

Figure 4.

Polygenic risk scores for adult IDH-mutant 1p/19q-codeleted glioma. (a) Risk score distributions from glioma cohorts of European and non-European ancestries. (b) Risk score distributions from nonglioma cohorts of European ancestry, including individuals in TCGA with primary tumor locations that are known to have the potential to metastasize to the brain. (c) Risk score distributions from nonglioma cohorts of non-European ancestry, including individuals in TCGA with primary tumor locations that are known to have the potential to metastasize to the brain. BRCA, Breast invasive carcinoma; CLL, chronic lymphocytic leukemia; COAD, colon adenocarcinoma; KIRC, kidney renal clear cell carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; READ, rectum adenocarcinoma; TCGA, The Cancer Genome Atlas.

Figure 5.

Polygenic risk scores for adult IDH-wildtype glioma. (a) Risk score distributions from glioma cohorts of European and non-European ancestries. (b) Risk score distributions from nonglioma cohorts of European ancestry, including individuals in TCGA with primary tumor locations that are known to have the potential to metastasize to the brain. (c) Risk score distributions from nonglioma cohorts of non-European ancestry, including individuals in TCGA with primary tumor locations that are known to have the potential to metastasize to the brain. BRCA, Breast invasive carcinoma; CLL, chronic lymphocytic leukemia; COAD, colon adenocarcinoma; KIRC, kidney renal clear cell carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; READ, rectum adenocarcinoma; TCGA, The Cancer Genome Atlas.